Genetics of neurological diseases

Abstract

This chapter examines the role of genetic changes in the etiology of neurological diseases, focusing particularly on autoimmune neurological diseases and neurodegenerative disorders. The genetic contributions to neurological diseases vary widely; for example, monogenic diseases are often associated with a single genetic mutation, whereas the etiology of polygenic diseases typically involves interactions between genetic factors and environmental influences. Despite identifying numerous common and rare variants in loci both within and outside the MHC associated with multiple sclerosis, a complex heritable autoimmune disease of the central nervous system, approximately half of its genetic components remain unknown. Genetic predispositions associated with peripheral nervous system autoimmune diseases such as Guillain-Barré syndrome, multifocal motor neuropathy, and myasthenia gravis are limited, highlighting gaps in understanding their genetic underpinnings. In neurodegenerative diseases like Alzheimer's disease, the ε4 isoform of the APOE gene has been shown to be a major allele increasing the risk, while other genetic factors are implicated in disease mechanisms. In Parkinson's disease, the influence of both monogenic and complex genetic components has been extensively studied, with genes like SNCA and LRRK2, along with numerous genetic variants, linked to disease risk. Over 50 disease-causing or modifying genes have been identified in amyotrophic lateral sclerosis, particularly pathogenic variants in genes such as SOD1, C9ORF72, TARDBP, and FUS are observed in familial cases, though the genetic causes of more than 90% of sporadic cases remain unknown. This section provides a broad overview of the genetic basis of neurological diseases, examining the role of genetic factors across different disease groups and discussing the place of next-generation sequencing technologies in their diagnosis, alongside ethical considerations in this context.